The enzyme, p70S6 kinase (p70S6K) is a serine-threonine kinase and a member of the AGC family. It is a downstream effector of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway and p70S6 undergoes phosphorylation and activation in response to growth factors such as IGF-I, EGF, TGF-[alpha] and HGF.
Activation of p70S6K in turn phosphorylates S6 ribosomal protein which promotes translation leading to an increase in protein synthesis in a cell. High levels of protein synthesis are required for cellular proliferation. It has also been shown that p70S6K has a necessary role in the mitotic cycle of a cell (Lane et al, Nature, 1993, 363(6425):170-2).
The kinase p70S6K has been shown to be constitutively activated in human tumour cells, leading to tumour cell proliferation. Inhibition of the p70S6K/mTOR pathway has been shown to lead to a decrease in tumour cell proliferation and an increase in tumour cell apoptosis (Pene et al (2002) Oncogene 21, 6587 and Le et al (2003) Oncogene 22, 484). Inhibition of p70S6K activity would therefore present an attractive approach for the treatment of cancer.
The mTOR/p70S6K pathway has been shown to be activated in renal cell carcinoma and is inhibited by CCI-779 (Robb, V. A.; Karbowniczek, M.; Klein-Szanto, A. J.; Henske, E. P. J Urol 2007, 177, 346-52). Furthermore, patients with gliobastoma multiforme whose tumours express high levels of phosphorylated p70S6K have been found to benefit from treatment with CCI-779 (Galanis, E.; Buckner, J. C.; Maurer, M. J.; Kreisberg, J. I.; Ballman, K.; Boni, J.; Peralba, J. M.; Jenkins, R. B.; Dakhil, S. R.; Morton, R. F.; Jaeckle, K. A.; Scheithauer, B. W.; Dancey, J.; Hidalgo, M.; Walsh, D. J. J Clin Oncol 2005, 23, 5294-304).
A significant linear association between disease progression and inhibition of p70S6K activity has been reported by Peralba et al [(2003) Clinical Cancer Research 9, 2887].
It would therefore be beneficial to develop compounds that have the ability to inhibit p70S6 kinase.